Our laboratory employs genomic technologies for identifying disease genes. We identified the gene (MEN1) responsible for multiple endocrine neoplasia type 1 (MEN1) syndrome in 1997. MEN1 is a familial cancer syndrome characterized by tumors in multiple endocrine tissues, primarily of the parathyroid, pancreas, and anterior pituitary. The amino acid sequence of the MEN1-encoded protein (menin) does not reveal any identifiable structural or functional motifs. We have developed mouse Men1+/- models displaying a tumor spectrum similar to that in humans, and thus allowing us to study the role of menin in tumorigenesis. Interestingly, homozygous loss of menin results in early embryonic lethality in mice illustrating the requirement of menin in early development and differentiation. We have found that menin resides primarily in the nucleus, and is involved in transcriptional regulation. Our efforts are focused on exploring the role(s) of menin in differentiation, organogenesis, and development and correlating this with the overall changes in expression associated with the loss or overexpression of menin. Menin-null MEF (mouse embryo fibroblst) cells showed a significant decrease in the expression of several extracellular matrix/cell adhesion protein genes including fibulin-2 (Fbln2), periostin (Postn), and versican (Cspg2, chondroitin sulfate proteoglycan). All three of these proteins, which showed reduced expression in the absence of menin, are critical for the developing heart, and thus explain the defective heart development observed in mouse embryos with the homozygous loss of menin. Menin interacts with MLL, the mixed lineage leukemia protein, and both are components of a COMPASS-like protein complex, regulating expression of Hox genes among others. MLL-null mouse embryonic stem (ES) cells are defective hematopoietic differentiation via dysregulation of Hox genes. We generated three menin-null ES clones, and found that they were deficient in their ability to generate mature hematopoietic colonies. Re-expression of either Men1 or Hoxa9 could rescue the defect. Global expression changes in menin-null ES cells during different stages of hematopoietic differentiation are being studied to evaluate the molecular changes mediated by menin in this differentiation of mesodermal lineages. We also evaluated whether loss of menin affects differentiation into endodermal lineages, using the pluripotent mouse P19 embryonic stem cells, with normal and reduced (shRNA-mediated) menin expression. Retinoic acid (RA) induces endodermal differentiation in P19 cells. However, cells with reduced menin expression were resistant to endodermal differentiation when stimulated with RA. On the other hand, menin overexpressing cells displayed characteristic endodermal phenotype by the acquisition of cytokeratin Endo A expression, a marker for the primitive endoderm. The P19 cells with reduced menin expression exhibited severe alteration in expression of several Hox genes and whether this contributes to the observed differences in differentiation needs to be studied. We have now discovered that loss of menin, mediated by siRNA, resulted in enhanced migration, and increased tube formation in HuVEC (human vascular endothelial cells), an indication of increased angiogenesis. We find increased expression of claudin-1, a tight junction membrane protein, in Men1 siRNA treated HuVECs, and this appears to mediate the increased angiogensis. We have used high-density SNP arrays to define the precise deletion boundaries in 2q37 deletion syndrome patients, characterized by several distinct physical features, and in some cases, developmental delay, obesity, hypotonia, and autism. We found the smallest deletion (<2 Mb) in a patient with minimal clinical characteristics, three cases (out of ten) where the 2q terminal deletion is also associated with duplication of the adjacent region, and a case with an interstitial deletion but intact telomeric region. A detailed evaluation of the deletion breakpoints is being pursued. We had identified amplification and overexpression of TRMT12 in breast cancer. TRMT12 is a human homolog of a yeast gene encoding an enzyme that catalyzes a step in the posttranscriptional modification of a G to a highly modified base, yW (wybutosine), present in tRNAPhe. We find that human TRMT12 can substitute for the homologous yeast gene in the yW biosynthetic pathway in yeast, and now identify the specific amino acids that are responsible for the enzyme activity. However, yW modification was unaffected in tRNAPhe from mouse mammary tumor model overexpressing TRMT12. We find that TRMT12 regulates the protein levels of SMG-1, a new member of the well-known PIKK kinase family. SMG-1 regulates non-sense mediated mRNA decay (NMD) as well as a key player in p53 mediated genotoxic stress response. The functional role(s) of TRMT12 in NMD and cellular response to DNA damage is being pursued. Fanconi anemia (FA), a recessive disorder invariably leading to bone marrow failure, also displays to some extent, hematologic malignancies and head and neck cancer. Biallelic inactivation of one of the 13 genes result in FA. Interestingly, inherited heterozygous mutations in four of these genes are known to increase susceptibility to breast or pancreatic cancer. We have initiated efforts to study the display of cancers associated with FA, and also the involvement of the FA genes in other cancers.